Mechanism-Specific Antiarrhythmic Effects of the Potassium Channel Activator Levcromakalim Against Repolarization-Dependent Tachycardias

Mechanism-Specific Action of Levcromakalim. Introduction: The hypothesis that levcromakalim. a potassium channel (I_K-ATP.) activator with antihypertensive properties, has a mechanism-specific antiarrhythmic action against repolarization-dependent ventricular tachycardias (VTs) was tested in dogs. Methods and Results: A low dose of leveromakalim (0.01 mg/kg) was selected, which decreased blood pressure by 25% but had almost no electrophysiologic effect on AV nodal or ventricular conduction or effective refractory period. In dogs with chronic AV block, the antiarrhythmic action of this dose of levcromakalim was evaluated in three models of abnormal impulse formation: (I) dsotalol (2 mg/kg) induced torsades de pointes VT, initiated by early afterdepolarizations (EADs). (2) sustained ouabain-induced VTs, which are dependent on delayed after depolarizations (DADs), and (3) VT occurring 24 hours after left anterior descending coronary artery occlusion, which are likely based on abnormal automaticity. Levcromakalim abolished d-sotalol induced U waves, ventricular ectopic beats, and self-terminating bouts of torsades de pointes. Induction of torsades de pointes by pacing was also completely prevented. The cycle length of the idioventricular rhythm, which was lengthened after d-sotalol from 1490 ± 515 to 1700 ± 610 msec (P < 0.05), remained similar after levcromakalim (1655 ± 580 msec). The QT(U) duration, which was increased after d-sotalol from 410 ± 55 to 550 ± 40 msec (P < 0.05), normalized to 405 ± 70 msec (P < 0.05). Lcvcromakulim did not suppress but rather enhanced ouabain-induced VT by decreasing the cycle length slightly from 315 ± 35 to 290 ± 35 msec (P < 0.05). Pretreatment with a beta Mocker prevented this acceleration in rate. Finally, levcromakalim had no effect on VT 24 hours after infarction. Conclusion: A low dose of levcromakalim has specific antiarrhythmic properties against repolarization-dependent arrhythmias, but it does not affect VTs based on other mechanisms of abnormal impulse formation.     

Indications and effects of botulinum toxin A for obstetric brachial plexus injury: a systematic literature review

Aim To give an overview of indications for the use of botulinum toxin A (BoNT‐A) treatment for children with obstetric brachial plexus injury (OBPI), and to present the best available evidence of the effectiveness of this treatment. Method Searches were performed in Cinahl, Cochrane Library, Embase, PubMed, and Web of Science, using the keywords ‘botulinum’ and ‘plexus’, to identify articles reporting on the use of BoNT‐A as a treatment for children with OBPI. Studies found through the references of related articles were also selected. Results Ten full‐text papers and six congress abstracts were included, involving 343 children. Four groups of indications could be identified: internal rotation/adduction contracture of the shoulder, limited active elbow flexion, limited active elbow extension, and pronation contracture of the lower arm. Overall, positive results were reported for all except the indication for limited active elbow extension. However, only one study was comparative in nature; all others were classified as having a low level of evidence. There was a large variation in outcome measures. Interpretation To provide better evidence for the already partly promising results of BoNT‐A treatment for children with OBPI, multicentre randomized controlled trials are needed.     

Pliable but not receptive: concerning the marginal influence of a medical psychology course on the socialization process of doctors

Growth into a professional role requires absorption of knowledge, the learning of skills and the adoption of behavioural patterns and values which are part of a particular profession. In sociological literature this is described as the socialization/professionalization process. In this article the research literature which describes the process is reviewed. However, apart from the many positive aspects of adjusting and conforming, there are also more negative developments in the learning behaviour and attitudes of the future doctor. The Department of Medical Psychology in Amsterdam has structured its teaching programme--in part--to overcome or to decrease such tendencies. This article deals with those parts of the course which attempt to influence medical students' interviewing and interpersonal skills. Research into the effects of this teaching points to a marginal influence in both areas. The author looks for explanations for this, in the light of the research literature. In conclusion, the direction is indicated which could further increase the influence of the medical psychology course on future doctors.     

Biological effects and receptor binding affinities of new pseudononapeptide bombesin/GRP receptor antagonists with N-terminal d-Trp or d-Tpi

In an attempt to produce more powerful (effective) bombesin/GRP receptor antagonists, the d forms of Trp or Trp analog (Tpi) were introduced at position 6 in two pseudononapeptides, Leu¹³Ψ (CH₂NH)Leu¹⁴-bombesin(6-14) and Leu¹³Ψ(CH₂NH)Phe¹⁴ -bombesin (6-14). These antagonists were tested for their ability to inhibit basal and gastrin releasing peptide (GRP) (14-27)-induced amylase release from rat pancreatic acini in a superfusion assay. They were also assessed for the inhibition of ¹²⁵I-Tyr⁴ -bombesin binding to Swiss 3T3 and small cell lung carcinoma cell line H-345 and the mitogenic response of Swiss 3T3 cells induced by GRP(14-27). The peptides, when given alone, did not stimulate amylase secretion, but were able to inhibit gastrin releasing peptide (14-27)-induced amylase release. All of the antagonists showed strong binding affinities for Swiss 3T3 and H-345 cells and suppressed the GRP(14-27)-induced increase of [³H]thymidine incorporation into DNA of Swiss 3T3 cells at nanomolar concentrations. Antagonist d -Tpi⁶,Leu¹³Ψ (CH₂NH)Leu¹⁴-bombesin (6-14)(RC-3095) was slightly more potent in these assays than d -Trp⁶,Leu¹³Ψ (CH₂NH)Leu¹⁴-bombesin (6-14)(RC-3125). Nevertheless, d -Trp⁶ Leu¹³Ψ (CH₂NH)Phe¹⁴-bombesin (6-14) showed the highest binding affinity for Swiss 3T3 and H345 cells and it was the most potent inhibitor of GRP(14-27)-induced amylase secretion. This antagonist RC-3420 was particularly effective in inhibiting the growth of Swiss 3T3 cells, exhibiting an IC₅₀ value less than 1 nm . Our work indicated that the substitution of d -Trp and d -Tpi at position 6 of the pseudononapeptide bombesin analogs (Ψ^13-14), in which the Met¹⁴ residue is replaced by Leu or Phe, results in potent bombesin/GRP antagonists with improved in vivo activity.